Water-dispersible coenzyme q10 dry powders

ABSTRACT

Novel powder compositions comprising droplets of Coenzyme Q-10 dispersed in a matrix of a modified polysaccharide or a gelatin are obtained by emulsifying Coenzyme Q-10 in a solution of the matrix components.

The present invention relates to water-dispersible compositions comprising Coenzyme Q-10. Coenzyme Q-10 which by systematical nomenclature is 6-Decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, in view of its physiological activity, is used a supplement for human and animal nutrition. However, Coenzyme Q-10 is practically insoluble in water and therefore, has a poor bioavailability when administered orally. Efforts have been made to increase the solubility of Coenzyme Q-10, e.g., by means of forming solutions or emulsions using solubilizers e.g. surfactants such as polysorbates or lecithin see U.S. Pat. No. 6,054,261 and U.S. Pat. No. 4,483,873; polyethoxylated hydrogenated castor oil, see EP 522 433; or decaglyceryl stearate, see JP 2000212066; by providing stabilized fine aqueous dispersions of the solid compound, see U.S. Pat. No. 6,197,349; or by forming micellar or liposomal aggregates of derivatives of the compound, see U.S. Pat. No. 4,883,670.

The present invention provides Coenzyme Q-10 formulations with improved bioavailability. In one aspect, the invention relates to novel powder compositions which comprise droplets of Coenzyme Q-10 which droplets are dispersed in a matrix of a modified polysaccharide or a gelatin. The invention further relates to novel aqueous emulsions of coenzyme Q-10 which is dispersed in a modified polysaccharide or gelatin matrix. Still further, the invention relates to food, beverages, feeds, cosmetics and pharmaceutical products comprising such Coenzyme Q-10 formulation.

In another aspect, the invention relates to a novel process for the preparation of novel powder compositions which comprise droplets of Coenzyme Q-10 which droplets are dispersed in a matrix of a modified polysaccharide or a gelatin.

The term “modified polysaccharide” refers to polysaccharides which contain a lipophilic moiety, e.g., a hydrocarbon moiety having a chain length of preferably 5 to 18 carbon atoms in the straight chain. Preferably the modified polysaccharide should be at least acceptable for animal consumption. For human consumption, preferred modified polysaccharides should be GRAS (generally recognized as safe) or an approved material for food consumption as determined by the various regulatory agencies world wide. A preferred modified polysaccharide is modified starch. Starches are hydrophilic and therefore do not have emulsifying capacities. However, modified starches are made from starches substituted by known chemical methods with hydrophobic moieties. For example starch may be treated with cyclic dicarboxylic acid anhydrides such as succinic and glutaric anhydrides, substituted with an alkyl or alkenyl group. A particularly preferred modified starch of this invention has a structure as depicted below

wherein St is a starch, R is an alkylene radical and R′ is a hydrophobic group. Preferably the alkylene radical is lower alkylene, such as dimethylene or trimethylene. R′ may be an alkyl or alkenyl group, preferably containing 5 to 18 carbon atoms. A preferred modified starch of formula I is starch sodium octenyl succinate. It is available commercially from, among other sources, National Starch and Chemical Company, Bridgewater, N.J. as Capsul®. Making this compound, and the compounds of Formula 1 in general, is known in the art (see “Modified Starches: Properties and Uses, ed. O. B. Wurzburg, CRC Press, Inc., Boca Raton, Fla. (1991)).

The term “gelatin” as used herein denotes any gelatin that may be obtained or produced, respectively, from skins or bones by acid or base hydrolysis. The preferred gelatin for use in the present invention is fish gelatin.

The composition of this invention may comprise up to about 60% by weight of Coenzyme Q-10 in the matrix on a dry weight basis. Preferably, the percentage of Coenzyme Q-10 in the matrix is from about 10% to about 40%, most preferably about 25% by weight.

The composition may also contain a small amount of residual water. The amount of residual water depends on the drying technology used, which will be evident to a skilled practitioner. The amount of residual water also depends on the proportion of the matrix material in the composition and may be up to about 10% of a composition having a high matrix proportion, and typically is about 5% by weight. Alternatively, other ingredients standard to a powder composition may be added, for example sucrose, maltodextrin or antioxidants alone or in combination, and the amounts of Coenzyme Q-10 and polysaccharide or gelatin adjusted accordingly.

The novel powder compositions according to the present invention can be produced by a process which comprises:

-   a) providing an aqueous solution of a modified polysaccharide or a     gelatin; -   b) adding coenzyme Q-10 to the solution of step a); -   c) emulsifying the product of step b) to obtain an emulsion of the     desired size of the droplets; and -   d) drying the emulsion of step c) to obtain a powder composition.

In one embodiment of the present invention, coenzyme Q-10 is heated to obtain a melt and is then added in molten form to a slightly warmed (e.g., at about 40 to 50° C.) solution of the matrix components, i.e. the modified polysaccharide or a gelatin. Suitably, an antioxidant such as dl-tocopherol is added to the Coenzyme Q-10 melt. If desired, further components such as sucrose or maltodextrin may be added to the matrix solution. The mixture is then emulsified using conventional equipment until the desired size of the emulsion particles is obtained.

In a particular embodiment of the process of this invention, the powder composition is produced by

-   aa) providing an aqueous solution of a modified polysaccharide or a     gelatin; -   bb) adding Coenzym Q-10 in molten form to an aqueous solution of a     modified polysaccharide or a gelatin with mixing to form a crude     emulsion, preferably a pre-emulsion having a solids content of from     about 30% to about 50%, more preferably of about 45%; wherein the     emulsion droplets have an average diameter of 2000 nm or smaller; -   cc) emulsifying the crude emulsion further in a high-pressure     homogenizer at a temperature of about 5° C. to about 75° C. and at a     pressure of about 600 bar to about 4000 bar; and -   dd) spray-drying the emulsion.

Step a) and aa), respectively, can be done at any reasonable temperature to ensure a rapid dissolution of the modified polysaccharide in water and to fully utilize its functionality.

To ensure complete dissolution of modified polysaccharide within a reasonable amount of time, heating to about 40° or 80° C. is preferable, after which the resulting solution may be conveniently cooled to about 40° C. Coenzym Q-10 is then added in molten form and the mixture is homogenized to a crude emulsion (for example by using a colloid mill or any other conventional mixing means) until the droplet size is preferably not greater than 2000 nm. Droplet size may be measured by any conventional particle size analyzer. A preferred measuring means is laser light scattering technique. The Malvern ZetaSizer (Malvern Instruments, Southborough, Mass.) is an example of a laser light scattering measuring device.

The crude emulsion is then further emulsified using high pressure homogenizing equipment and vessels for this purpose. The device selected should provide a sufficiently high pressure. The high pressure homogenizing device, such as model DeBEE 2000 from BEE International (Migdal Ha'emek, Israel), is suitable for this purpose. It is also possible to use a water jet (such as those produced by Jet Edge Inc., Minneapolis, Minn.). The crude emulsion may be transferred from the holding vessel to the emulsifying device through a suitable sieve in order to prevent from clogging of the high pressure homogenizer. The temperature at which the homogenization (by which is meant further emulsification) takes place is best kept above room temperature e.g., between about 30° up to about 75° with a cooling system such as an ice water bath to control the temperature at high pressures. The pressure pump of the emulsifying device should be set at a suitable pressure (600 to 4000 bar depending on the desired droplet size).

Homogenization continues for a sufficient number of passes to obtain an emulsion of the desired droplet size. In general, the stabler the process pressure, the fewer number of passes should be required to achieve the same droplet size. The emulsion is then dried to obtain the powder of this invention. Drying may be accomplished by any standard method, for example spray-drying in a suitable spray dryer, such as Model Mobile Minor from Niro/AS (Soeborg, Denmark).

In order to attain the desired droplet size, the emulsion step cc) may be repeated through one or more passes as necessary to obtain the desired droplet size, i.e. the crude emulsion is passed into the homogenization vessel, emulsified, passed out of the homogenization vessel, and passed through the homogenization vessel again until the desired droplet size is attained. Usually up to twenty passes will be required depending on the emulsification pressure used. These passes are usually all performed at the same pressure and the same system parameters, but different pressures may be used for different passes (other system parameters could also be varied for different passes). The period of time for one pass is not critical. The amount of time per pass will depend on system parameters including emulsion viscosity, batch size, flow rate and pressure. These parameters will depend on the precise processing format selected, and may be varied by the skilled person to obtain the desired results. Emulsification passes should continue until testing shows that the desired droplet size is achieved as determined by particle size analysis. Suitably, the average droplet size of the Coenzyme Q-10 emulsion of this invention is not greater than about 500 nm, preferably less than about 200 nm and most preferably 130 nm or less. To obtain a droplet diameter of 130 nm or less it is important that the homogenization step be performed at an ultra-high pressure as described above to effectively reduce the droplet size of the emulsion to a desirable size. The pressure used in the homogenizer is preferably higher than 1000 bar and most preferably higher than 1500 bar. The homogenization temperature as measured at the exit of the homogenizer is preferably below 70° C. The emulsion is then converted to a powder, by a known technology such as freeze-drying, fluid-bed drying, beadlet formation, but preferably by spray-drying, to obtain a powder composition which comprises droplets of Coenzym Q-10 having a diameter of not greater than about 500 nm, preferably less than about 200 nm and most preferably 130 nm or less and which are dispersed in the matrix.

The Coenzym Q-10 compositions of this invention can be used to fortify food and beverages. The can also be used in pharmaceutical compositions designed to provide a supply for Coenzyme Q-10. Beverages fortified with Coenzyme Q-10 can be obtained by adding to a beverage a powder composition of this invention. Adding a powder composition of this invention to a liquid requires no special procedure or extensive mixing. The powder may simply be added to the liquid and mixed by shaking or stirring until the powder particles are no longer visible to the naked eye.

The powder compositions of this invention may also be added to cosmetics if it is desired to blend Coenzyme Q-10 into a cosmetic. If the cosmetic is optically clear, preferred compositions of this invention may be used to avoid increasing the turbidity of the cosmetic. Cosmetics include any materials designed for application to the skin, hair, or nails, for example skin care products such as balms, lotions, or sticks, various ointments, make-up compositions for use on the face, eyes, or lips, shampoos and conditioners, nail polishes, and the like. The cosmetic may contain other active ingredients. Pharmaceutical compositions intended for topical application in the form of ointments, lotions, and the like are also contemplated. Cosmetic formulations will be well known to the skilled person. The powder composition of this invention is added at an appropriate time in the production process such as to be thoroughly blended into the cosmetic.

The following examples served to demonstrate the present invention) but are not intended to limit it in any way.

EXAMPLE 1

58 g of fish gelatin (bloom number 0) and 58 g of sucrose were placed in a 500-ml vessel and 60 ml of de-ionized water was then added. The mixture was brought into solution while stirring with a mincer disc. at 1000 rpm at 40° C., which gave the matrix. 40 g of coenzyme Q-10) mixed with 2 g of dl-α-tocopherol, was melted at 55° C. Thereupon, this mixture were emulsified in the matrix and stirred for 15 minutes. During the emulsification and stirring the mincer disc was rotated at 4800 rpm. After this time the internal phase of the emulsion had an average particle size of about 260 nm. The emulsion was then diluted with 70 ml of de-ionized water and heated to 60° C. Subsequently 1300 g of corn starch were placed in a laboratory spray tank and cooled to at least 0° C. The emulsion was sprayed into the spray tank using a rotating spray nozzle. The thus-obtained particles plus the corn starch were sieved (sieve fraction 160 to 630 μm) to remove the excess corn starch and the particles were then dried at room temperature using a stream of air to yield 237 g dry particles, which contained 16.3% coenzyme Q-10.

EXAMPLE 2

In an experiment analogous to Example 1, the fish gelatin was replaced with a starch sodium octenyl succinate (National Starch and Chemical Company, Bridgewater, N.J.). The particle size of the inner phase was about 160 nm. The yield was 288 g and the coenzyme Q-10 content was 13.4%.

EXAMPLE 3

267.4 g of starch sodium octenyl succinate (National Starch and Chemical Company, Bridgewater, N.J.) is dissolved in 287.8 g of deionized water at 80° C. After the starch solution is cooled to about 40° C., a solution of 50 g of coenzyme Q-10 and 2.5 g of dl-α-tocopherol, which is prepared at 55° C., is gradually added to the starch sodium octenyl succinate solution and homogenized with a lab homogenizer until the droplet size of the emulsion is not greater than 2000 nm. The crude emulsion is then homogenized with a high pressure homogenizer at 2000 bar. The emulsion is recycled through the homogenization process until the droplets of the emulsion reaches 130 nm or below.

The emulsion may be spray-dried (Niro A/S, Soeorg, Denmark, Model Mobile Minor) to yield a powder containing about 15% of Coenzyme Q-10. 

1. A powder composition comprising droplets of Coenzyme Q-10 dispersed in a matrix of a modified polysaccharide or a gelatin.
 2. A powder composition of claim 1 wherein the matrix is a modified polysaccharide.
 3. A powder composition of claim 2 wherein the modified polysaccharide is a modified starch.
 4. A powder composition of claim 3 wherein the modified starch is starch sodium octenyl succinate.
 5. A powder composition of claim 1 wherein the matrix is a gelatin.
 6. A powder composition of claim 1 wherein the gelatin is fish gelatin.
 7. A powder composition of claim 1 wherein the matrix further comprises a mono- or disaccharide, or a polysaccharide.
 8. A powder composition of claim 7 wherein the matrix further comprises sucrose.
 9. A powder composition of claim 7 wherein the matrix further comprises maltodextrin.
 10. A powder composition of claim 1 wherein the amount of coenzyme Q-10 is from about 1% to about 60% by weight (based on dry weight).
 11. A powder composition of claim 1 wherein the amount of coenzyme Q-10 is from about 10% to about 40% by weight (based on dry weight).
 12. An aqueous emulsion composition comprising droplets of coenzyme Q-10 dispersed in an aqueous solution of modified polysaccharide or gelatin.
 13. An emulsion composition of claim 12 wherein the average droplet diameter is about 500 nm or less.
 14. An emulsion composition of claim 12 wherein the average droplet diameter is about 200 nm or less.
 15. An emulsion composition of claim 12 wherein the average droplet diameter is about 130 nm or less.
 16. A beverage or food comprising a powder composition according to claim
 1. 17. A process for producing a powder composition comprising droplets of coenzyme Q-10 dispersed in a matrix of a modified polysaccharide or a gelatin, comprising a) providing an aqueous solution of a modified polysaccharide or a gelatin; b) adding coenzyme Q-10 to the solution of step a); c) emulsifying the product of step b) to obtain an emulsion of the desired size of the droplets; and d) drying the emulsion of step c) to obtain a powder composition.
 18. A process for producing a powder composition comprising droplets of coenzyme Q-10 dispersed in a matrix of a modified polysaccharide or a gelatin, comprising aa) providing an aqueous solution of a modified polysaccharide or a gelatin; bb) adding Coenzyme Q-10 in molten form to the aqueous solution of step aa) with mixing to form a crude emulsion, wherein the emulsion droplets have an average diameter of 2000 nm or smaller; cc) emulsifying the crude emulsion further in a high-pressure homogenizer at a temperature of about 5° C. to about 75° C. and at a pressure of about 600 bar to about 4000 bar; and dd) spray-drying the emulsion.
 19. (canceled)
 20. A beverage or food comprising an emulsion composition according to claim
 12. 21. A process according to claim 18, wherein the crude emulsion has a solids content of from about 30% to about 50%.
 22. A process according to claim 21, wherein the crude emulsion has a solids content of about 45%. 